This project within the P20 application is: Neural Effects of Chronic Cannabis Exposure in Human Adolescents. The overall hypothesis is that dysregulation of frontal cortex function by cannabis use impairs executive cognitive function, thereby increasing vulnerability to cannabis dependence. As adolescence is characterized by ongoing brain development, this may be a particularly vulnerable period. Thus, brain functioning will be characterized in human adolescents ages 15-17 to evaluate brain and behavioral abnormalities associated with chronic cannabis use using neuropsychological testing and functional magnetic resonance imaging (fMRI). Cannabis users (n=30) and demographically similar normal controls (n=30) will be free from psychiatric or neurological problems or substantial other substance involvement, and users will have >200 lifetimes exposures to cannabis. All youths will receive (1) neuropsychological testing focused on inhibition, verbal learning, and other executive functions as well as (2) fMRI during an inhibitory task previously shown to activate prefrontal regions, and during administration of Cambridge Neuropsychological Test Automated Battery (CANTAB) tasks that involve frontal regions and have non-human primate analogs. Then, youths will undergo a 28-day monitored abstinence period involving coming to the research site 9 times in 28 days for provision of an observed sample for urine drug screening. Each week, a brief battery of repeatable CANTAB tests will be administered, and subjective ratings of cannabis withdrawal, mood state, cortisol, and sleep quality will be collected. On the 27 day, subjects will repeat the full neuropsychological battery, and on the 28th day, participants will be given the same fMRI protocol. MANCOVA will contrast test performance and prefrontal brain response between groups and across time, controlling for potential confounds. To evaluate developmental differences in duration and chronicity of cannabis exposure, data will be contrasted directly with similar measures administered in Dr. Mason's project within this P20 application. Results will also be compared to those of adolescent non-human primates and rodents from the Center projects of Drs. Taffe and Parsons, respectively. Together, these projects and the infrastructure and training of the Center will help identify mechanisms for vulnerability to cannabis dependence, and characterize the potential neurotoxic abnormalities associated with chronic heavy cannabis use in youth.